Hippo signaling plays key roles in organ size control and tumor suppression. The signal transduction involves a core kinase cascade, including MST1/2 and Lats1/2 kinases, leading to YAP/TAZ phosphorylation, cytoplasmic retention and inhibition3. Physiological or pathological inactivation of these kinases leads to YAP/TAZ dephosphorylation and nuclear accumulation. Subsequently, nuclear YAP/TAZ binds to the TEA domain transcription factors (TEAD1-4 in mammals, and Scalloped in Drosophila) to mediate the target genes expression. The TEAD-YAP complex regulates normal development of skin, muscle, lung and liver, and are also oncogenic factor amplified in many human cancers. TEADs can also bind to Vgll4, which has been implicated as a tumor suppressor by competing with YAP/TAZ for TEADs binding. Therefore, TEADs are essential in regulating the transcriptional output of Hippo pathway. Although targeting TEAD-YAP could be a promising therapeutic approach for diseases with deregulated Hippo pathway, it remains challenging to directly inhibit transcription factors with small molecules. Therefore, understanding the regulation of TEADs might reveal new therapeutic opportunities for drug discovery.
Post-translational S-palmitoylation attaches a 16-carbon palmitate to the cysteine residue through a reversible thioester bond. A large number of palmitoylated proteins have been identified through proteomic studies. Dynamic S-palmitoylation plays critical roles regulating the trafficking, membrane localization and functions of many proteins, including Src-family kinases, GTPases, and synaptic adhesion molecules. Asp-His-His-Cys (DHHC) family proteins are evolutionarily conserved protein palmitoyl acyltransferases (PATs), mediating enzymatic S-palmitoylation. In addition, some proteins could bind to palmitoyl-Coenzyme A (CoA) directly, and undergo PAT-independent autopalmitoylation. However, autopalmitoylation is poorly characterized. Most of the reported examples of autopalmitoylation are observed under non-physiological, high concentration of palmitoyl-CoA (>100 μM). To date, only a few proteins, including yeast transporter protein Bet3, are autopalmitoylated under physiological concentrations of palmitoyl-CoA (1-10 μM). Therefore, it is important to reveal additional autopalmitoylated proteins and to understand their regulations and functions.